Administration form for pharmaceutically active peptides with sustained release and method for the production thereof

ABSTRACT

The invention relates to pharmaceutical administration forms with sustained release comprising at least one pharmacologically active peptide. The invention also relates to a method for the production thereof, a kit comprising a lyophilised peptide and an aqueous solution of an inorganic salt or acetic acid salt and the use of an aqueous solution of an inorganic or acetic acid salt for producing a pharmaceutical administration form which releases peptides in a continuous manner over a long period of time.

FIELD OF THE INVENTION

The invention relates to pharmaceutical administration forms withsustained release of active ingredient having at least onepharmacologically active peptide, to a method for the productionthereof, to a kit including a lyophilized peptide and an aqueoussolution of an inorganic salt or acetic acid salt and to the use of anaqueous solution of an inorganic or acetic acid salt for producing apharmaceutical administration form which displays sustained peptiderelease over a prolonged period.

DESCRIPTION OF THE PRIOR ART

The following pharmaceutical administration forms with sustained releaseof the pharmaceutically active peptide are known in the art:

-   -   1. Pharmaceutical administration forms with micro-encapsulated        and/or incorporated and/or conjugated pharmaceutically active        peptides in a biodegradable polymeric matrix (e.g. described in:        Maulding, H. V., J. Controlled Release (1987), 6, 167-76;        Siegel, R. A., Langer, R. Pharm. Res. (1984), 1, 2-10; Patent WO        9832423, Patent WO 2001078687).    -   2. Pharmaceutical administration forms including from scarcely        water-soluble complexes of the pharmaceutically active peptide        and an organic carrier molecule, such as, for example,        polysaccharides (e.g. described in: Patent WO 2000047234).

In both cases, enzymatic degradation of matrix or complex leads to thesustained release of the peptide.

PROBLEMS ASSOCIATED WITH THE PRIOR ART

Production of the known microcapsules or particles and insolublecomplexes of the peptide compounds require very demanding procedures inorder to obtain administration forms with sustained release of activeingredient. Normally, insoluble or slightly soluble compounds areproduced through precipitation of the peptide compound with thecounterion. The precipitate is collected by filtration andcentrifugation, washed with water and dried. In most cases, the solidmaterial is then powdered. All the individual steps in the productionmethod must be carried out under GMP conditions in an aseptic workingarea in order to make it possible in this way to guarantee the sterilityof the final product.

In the procedures for producing microcapsules, more or less toxicorganic solvents are used in order to dissolve the biodegradable polymermatrix. The dissolved active substance and the polymers of the matrixare then emulsified. After evaporation of the organic solvent, theparticles or the microcapsules are separated, washed and dried.

DESCRIPTION OF THE INVENTION

It has now surprisingly been found that administration forms withsustained release of active ingredient for pharmaceutically activepeptides are obtained by reconstituting a lyophilized peptide compoundwith a low-concentration inorganic salt solution before administration,with the amount of lyophilized peptide compound being chosen so that thepeptide solution or suspension after reconstitution is highlyconcentrated.

As a possible explanation, it is presumed that under these conditionsthere is controlled development of aggregates of the peptide compounds,which shows or show delayed dissolution. The result is then the foundsustained release of this active ingredient into the circulation. Inthis case, the formation of the aggregates leads to a colloidaldispersion whose viscosity are influenced by the concentration of thepeptide compound, the salt concentration and the standing time afterreconstitution.

According to the present invention, pharmaceutical gel preparationsincluding at least one pharmaceutically active ionic peptide compoundare mixed in a predetermined amount of the value X_(optimum) (in mg ofpeptide per ml of the preparation) with an aqueous solution of aninorganic or acetic acid salt in a predetermined concentration of thevalue Y_(optimum) (in % weight/volume), it being possible after themixing for administration to take place immediately or for a standingtime of up to about 120 minutes to be observed, and it being possiblefor the value X_(optimum) to be selected by a test method A includingthe stages of administration of various amounts X_(n) (number ofdifferent amounts n, where n≧1) (in mg) of the peptide as a mixture withan isotonic aqueous solution of mannitol onto or to a test system andselection of the amount X_(optimum) (in mg of peptide per ml of mixture)which provided in the experiment the most favorable blood plasma levelsof the peptide in the test system in relation to C_(max) (maximum bloodplasma concentration) and t_(max) (time until C_(max) is reached), andthe concentration Y_(optimum) being selected by a test method Bincluding the stages of administration of the amount X_(optimum) (in mgof peptide per ml of mixture) of the peptide as a mixture with aqueoussolutions which differ in the concentration Y_(n) (number of differentconcentrations n, where n≧1) (in % weight/volume) onto or to a testsystem and selection of the concentration Y_(optimum) (in %weight/volume) was fixed as the concentration which in the experimentresulted in the highest value for the plasma concentration C_(active),where C_(min)<C_(active)>C_(max) (C_(min)=lowest plasma concentration ofthe peptide at which the peptide still has an adequate pharmaceuticaleffect in the experiment). At the same time, it has an influence on thetime t_(active) until the highest concentration in the plasma isreached, where t_(active)>t_(max), provided.

A further embodiment provides a pharmaceutical preparation characterizedin that the pharmaceutically active ionic peptide compound is cationic.

A further embodiment provides a pharmaceutical preparation characterizedin that the pharmaceutically active ionic peptide compound is anionic.

A further embodiment provides a pharmaceutical preparation characterizedin that the pharmaceutically active ionic peptide compound is a mono-,di- or multivalent cationic or anionic peptide.

A further embodiment provides a pharmaceutical preparation characterizedin that the pharmaceutically active ionic peptide compound is a mono-,di- or multivalent ampholytic peptide.

A further embodiment provides a pharmaceutical preparation characterizedin that the pharmaceutically active ionic peptide compound has a lengthof from 5 to 20 amino acids.

A further embodiment provides a pharmaceutical preparation characterizedin that the pharmaceutically active ionic peptide compound has a lengthof from 8 to 12 amino acids.

A further embodiment provides a pharmaceutical preparation characterizedin that the pharmaceutically active ionic peptide compound is a GnRHanalog.

A further embodiment provides a pharmaceutical preparation characterizedin that the pharmaceutically active ionic peptide compound is a GnRHantagonist.

A further embodiment provides a pharmaceutical preparation characterizedin that the pharmaceutically active ionic peptide compound has beenselected from the group consisting of cetrorelix, teverelix, abarelix,ganirelix, azaline B, antide, detirelix, ramorelix, degarelix, D-63153or their pharmaceutically active salt or mixtures thereof.

A further embodiment provides a pharmaceutical preparation characterizedin that the pharmaceutically active ionic peptide compound is the GnRHantagonist D-63153.

A further embodiment provides a pharmaceutical preparation characterizedin that the inorganic salt or the acetic acid salt is a physiologicallytolerated salt.

A further embodiment provides a pharmaceutical preparation characterizedin that aqueous inorganic salt or acetic acid salt has been selectedfrom the group consisting of sodium chloride, calcium chloride,magnesium chloride, sodium acetate, calcium acetate and magnesiumacetate.

A further embodiment provides a pharmaceutical preparation characterizedin that the mixture of the pharmaceutically active ionic peptidecompound and the aqueous solution of the inorganic salt or of the aceticacid salt is a liquid suspension or a semisolid dispersion.

A further embodiment provides a pharmaceutical preparation characterizedin that the amount X of the pharmaceutically active ionic peptidecompound is in the range from about 5 to about 50 mg per ml of the totalamount of the pharmaceutical preparation.

A further embodiment provides a pharmaceutical preparation characterizedin that the amount X of the pharmaceutically active ionic peptidecompound is in the range from about 10 to about 50 mg per ml of thetotal amount of the pharmaceutical preparation.

A further embodiment provides a pharmaceutical preparation characterizedin that the amount X of the pharmaceutically active ionic peptidecompound is in the range from about 20 to about 30 mg per ml of thetotal amount of the pharmaceutical preparation.

A further embodiment provides a pharmaceutical preparation characterizedin that the amount X of the pharmaceutically active ionic peptidecompound is in the range from about 25 mg per ml of the total amount ofthe pharmaceutical preparation.

A further embodiment provides a pharmaceutical preparation characterizedin that D-63153 is the pharmaceutically active ionic peptide compound,and the amount X is in the range from about 5 to about 50 mg per ml ofthe total amount of the pharmaceutical preparation.

A further embodiment provides a pharmaceutical preparation characterizedin that D-63153 is the pharmaceutically active ionic peptide compound,and the amount X is in the range from about 10 to about 50 mg per ml ofthe total amount of the pharmaceutical preparation.

A further embodiment provides a pharmaceutical preparation characterizedin that D-63153 is the pharmaceutically active ionic peptide compound,and the amount X is in the range from about 20 to about 30 mg per ml ofthe total amount of the pharmaceutical preparation.

A further embodiment provides a pharmaceutical preparation characterizedin that D-63153 is the pharmaceutically active ionic peptide compound,and the amount X is in the region of about 25 mg per ml of the totalamount of the pharmaceutical preparation.

A further embodiment provides a pharmaceutical preparation characterizedin that the concentration Y of the aqueous inorganic or acetic acid saltsolution is equal to or less than 0.9% (weight/volume).

A further embodiment provides a pharmaceutical preparation characterizedin that the concentration Y of the aqueous inorganic or acetic acid saltsolution is in the range from about 0.01% to about 0.9% (weight/volume).

A further embodiment provides a pharmaceutical preparation characterizedin that the concentration Y of the aqueous inorganic or acetic acid saltsolution is in the range from about 0.05% to about 0.5% (weight/volume).

A further embodiment provides a pharmaceutical preparation characterizedin that the concentration Y of the aqueous inorganic or acetic acid saltsolution is about 0.1% (weight/volume).

A further embodiment provides a pharmaceutical preparation characterizedin that the inorganic salt is sodium chloride and in that theconcentration Y is equal to or less than about 0.9% (weight/volume).

A further embodiment provides a pharmaceutical preparation characterizedin that the inorganic salt is sodium chloride and in that theconcentration Y is in the range from about 0.01% to about 0.9%(weight/volume).

A further embodiment provides a pharmaceutical preparation characterizedin that the inorganic salt is sodium chloride and in that theconcentration Y is in the range from about 0.05% to about 0.5%(weight/volume).

A further embodiment provides a pharmaceutical preparation characterizedin that the inorganic salt is sodium chloride and in that theconcentration Y is about 0.1% (weight/volume).

A further embodiment provides a pharmaceutical preparation characterizedin that at least one of the pharmaceutically active ionic peptidecompound is D-63153, and the inorganic salt is sodium chloride.

A further embodiment provides a pharmaceutical preparation characterizedin that at least one of the pharmaceutically active ionic peptidecompound is D-63153, and the amount X thereof is about 25 ml per ml ofthe preparation, and in that the inorganic salt is sodium chloride, andthe concentration Y thereof is about 0.1% (weight/volume).

A further aspect of the invention provides a method for producing apharmaceutical preparation including the steps A) bringing together anamount X_(optimum) (in mg per ml of the finished preparation) of atleast one pharmaceutically active peptide compound in lyophilized formand an aqueous solution of an inorganic or acetic acid salt in aconcentration with the value Y_(optimum) (% weight/volume) and A) mixingthe components.

A further embodiment of the invention provides a method for producing apharmaceutical preparation, characterized in that the pharmaceuticallyactive ionic peptide compound is D-63153, and the inorganic salt issodium chloride.

A further embodiment of the invention provides a method for producing apharmaceutical preparation, characterized in that the pharmaceuticallyactive ionic peptide compound is D-63153, and the amount thereof isabout 25 mg/ml, and in that the organic salt is sodium chloride, and theconcentration thereof is about 0.1% (weight/volume).

A further embodiment of the invention provides a method for producing apharmaceutical preparation, characterized by further including the stepof sterilization of the peptide formulation by irradiation with gammarays or electron beams takes place.

A further embodiment of the invention provides a method for producing apharmaceutical preparation, characterized in that the production of thepeptide formulation takes place with use of aseptic procedures.

A further aspect of the invention provides a kit for producing apharmaceutical preparation, including a previously fixed amount X (in mgper ml of the finished preparation) of a pharmaceutically active ionicpeptide compound in lyophilized form and of an aqueous solution of aninorganic or acetic acid salt in a previously fixed concentration Y %(weight/volume).

A further embodiment of the invention provides a kit for producing apharmaceutical preparation, characterized in that the pharmaceuticallyactive peptide compound is D-63153 in lyophilized form.

A further embodiment of the invention provides a kit for producing apharmaceutical preparation, characterized in that the D-63153lyophilizate additionally comprises mannitol.

A further embodiment of the invention provides a kit for producing apharmaceutical preparation, characterized in that the inorganic salt issodium chloride.

A further embodiment of the invention provides a kit for producing apharmaceutical preparation, characterized in that the amount X ofD-63153 is about 25 mg per finished preparation and the concentration ofthe aqueous sodium chloride solution is about 0.1% weight/volume.

A further aspect of the invention provides a method for treating apatient with a pharmaceutically active peptide compound, characterizedin that a pharmaceutical preparation as claimed in any of theaforementioned claims is administered subcutaneously or intramuscularlyto the patient by means of a syringe.

A further embodiment of the invention provides a method for treating apatient with a pharmaceutically active peptide compound, characterizedin that the administered pharmaceutical preparation displays a sustainedpharmaceutical activity.

A further embodiment of the invention provides a method for treating apatient with a pharmaceutically active peptide compound, characterizedin that the administered pharmaceutical preparation displays a sustainedpharmaceutical activity for at least 4 weeks.

A further embodiment of the invention provides a method for treating apatient with a pharmaceutically active peptide compound, characterizedin that the administered pharmaceutical preparation displays a sustainedpharmaceutical activity for at least 8 weeks.

A further embodiment of the invention provides a method for treating apatient with a pharmaceutically active peptide compound, characterizedin that the administered pharmaceutical preparation displays a sustainedpharmaceutical activity for at least 12 weeks.

A further embodiment of the invention provides a method for treating ahormone-dependent disorder of a patient by subcutaneous or intramuscularadministration of the aforementioned pharmaceutical preparations in apatient requiring this.

A further aspect of the invention provides a method for treatingprostate cancer in a patient by subcutaneous or intramuscularadministration of the pharmaceutical preparation of the inventiondescribed above to a patient requiring this.

A further aspect of the invention provides a method for treating breastcancer in a patient by subcutaneous or intramuscular administration ofthe pharmaceutical preparation of the invention described above to apatient requiring this.

A further aspect of the invention provides a method for treating uterinemyomas in a patient by subcutaneous or intramuscular administration ofthe pharmaceutical preparation of the invention described above to apatient requiring this.

A further aspect of the invention provides a method for treatingendometriosis in a patient by subcutaneous or intramuscularadministration of the pharmaceutical preparation of the inventiondescribed above to a patient requiring this.

A further aspect of the invention provides a method for treatingprecocious puberty in a patient by subcutaneous or intramuscularadministration of the pharmaceutical preparation of the inventiondescribed above to a patient requiring this.

A further aspect of the invention provides a method for modifying thereproductive function in a patient by subcutaneous or intramuscularadministration of the pharmaceutical preparation of the inventiondescribed above to a patient requiring this.

A further aspect of the invention provides a pharmaceutical preparation,characterized in that the mixture of the pharmaceutically active ionicpeptide compound and of the aqueous solution of the inorganic salt or ofthe acetic acid salt is a molecular-dispersed or colloidal mixture whichmay be of liquid to semisolid consistency.

A further aspect of the invention provides a pharmaceutical preparation,characterized in that a colloidal dispersion is formed byreconstitution.

A further aspect of the invention provides a pharmaceutical preparation,characterized in that a colloidal dispersion is formed by storage orleaving to stand after reconstitution and changes its viscosity as afunction of time and thus improves the reproducibility of the delayedrelease of active ingredient.

A further aspect of the invention provides a kit including a lyophilizedpharmaceutically active peptide, for example D-63153, where appropriatetogether with one or more pharmaceutically acceptable excipients oradditives, and a low-concentration aqueous solution of an inorganicsalt, preferably sodium chloride.

In a preferred embodiment, the peptide compound of the administrationform is a GnRH analog, even better a GnRH antagonist, and the inorganicsalt is a highly soluble physiological salt, preferably sodium chloride.Because of the parenteral administration, it is necessary for thepowdered peptide compound and the solution for the reconstitution to besterile.

The present invention makes it possible easily to produce suspensionswith sustained release of a peptide compound active ingredient,preferably of a GnRH antagonist. This is obtained by reconstituting ahighly concentrated lyophilizate of the peptide compound comprisingmannitol with a dilute inorganic salt solution (e.g. sodium chloridesolution).

Formation of the pharmaceutical formulation of the invention is moreoverdependent on the following parameters:

-   -   1. the concentration of the peptide compound in the solution        after reconstitution    -   2. the concentration of the inorganic salt in the solvent        employed for reconstitution    -   3. the standing time of the solution after reconstitution and        the extent of aggregation obtained thereby, which is reflected        by the viscosity increase.

The high concentration of the peptide compound leads to aggregationthereof, which can be controlled by adding an inorganic salt solution.The solubility of the peptide compound decreases as the saltconcentration increases. The colloidal properties become more prominentthan the solution properties, as is clear from the increasing viscosityeven as far as a gel. The “gel” in this connection represents abicoherent system consisting of the peptide aggregate as the solid phaseand water as the liquid phase.

The administration forms of the invention for pharmaceutically activepeptides with sustained release of active ingredient are always in theform of a gel before administration.

In an ideal range of salt concentration, combined with a suitable amountof peptide compounds, sustained release of active ingredient can beobtained for a period of 4 weeks or more.

Any physiologically tolerated inorganic salt can be used for theinorganic salt solution, preferably sodium chloride.

The reconstitution takes place with a low-concentration salt solution.The concentration should in this case be equal to or less than about0.9% (weight/volume), preferably in the range from about 0.01% to about0.9%, particularly preferably in the range from about 0.05 to about 0.5%(weight/volume), very preferably about 0.1% (weight/volume).

A low-concentration sodium chloride solution with a sodium chlorideconcentration in the range from about 0.05 to about 0.5%(weight/volume), preferably of about 0.1% (weight/volume) is preferred.

The peptide in the formulation is a pharmacologically active peptidecompound which may be a mono-, di- or multivalent cationic or anionicpeptide. The peptide may consist of from 5 to 20 amino acids in length,more preferably from 8 to 12 amino acids in length. More in detail, thepeptide compound is a GnRH analog and the GnRH analog is a GnRHantagonist. Examples of GnRH analogs are cetrorelix, teverelix(Deghenghi et al., Biomed & Pharmacother 1993, 47, 107), abarelix(Molineaux et al., Molecular Urology 1998, 2, 265), ganirelix (Nestor etal., J. Med. Chem. 1992, 35, 3942), azaline B, antide, A-75998 (Cannonet al., J. Pharm. Sci. 1995, 84, 953), detirelix (Andreyko et al., J.Clin. Endocrinol. Metab. 1992, 74, 399), RS-68439, ramorelix (Stockemannand Sandow, J. Cancer Res. Clin. Oncol. 1993, 119, 457), degarelix(Broqua, P.: Riviere et al., JPET 301, 95), D-63153 (PCT: EP00/02165).

The structures of the abovementioned GnRH analogs are depicted forexample in the abovementioned references and in the following reviewarticles: Behre et al., GnRH antagonists: an overview, Proceedings ofthe 2nd World Conference on Ovulation Induction, The ParthenonPublishing Group Ltd, UK; Kutscher et al., Angew. Chem. 1997, 109, 2240.

The compound D-63 153 is described inter alia in German patentapplication No. DE 199 11 771.3. The physico-chemical data aresummarized in FIG. 6.

The concentration of the pharmaceutically active peptide may be in therange from about 5 mg/ml to about 50 mg/ml, preferably about 10 mg/ml toabout 50 mg/ml, particularly preferably about 20 mg/ml to about 30 mg/mland very particularly preferably about 25 mg/ml (ml=total volume of thefinished administration form).

All pharmaceutically active peptides can be employed in theconcentrations mentioned. The peptide D-63 153 is particularlypreferred.

A further aspect of the present invention provides a method forproducing administration forms for pharmaceutically active peptides withsustained release of active ingredient.

According to the invention, the acetate salt base of the peptidecompound is completely dissolved in aqueous acetic acid until a clearsolution is formed. The solution is diluted with water for injections,which receives the necessary amount of mannitol so that an isotonicsolution which can be administered is formed. After sterilizingfiltration of the solution it is dispensed into vials and lyophilized.

A sodium chloride solution (e.g. 0.1%) is used for reconstitution beforeadministration in order thus to control the aggregation of the peptideand therefore also the solubility. The reconstitution takes place whereappropriate by careful swirling or shaking, it being necessary to avoidfoaming.

The pharmaceutical administration forms of the invention permitsustained delivery of the peptide compound after administration of theadministration form in the subject. The duration and extent of deliverycan be varied by changing the concentrations of peptide compound and theconcentration of the salt used.

The standing time after reconstitution is also important for the releaseof the peptide active ingredient. The standing time may be between about0 to about 120 min, preferably between about 10 to about 120 minutes,particularly preferably between about 15 to 60 minutes. It has beenfound that the colloidal system obtained by aggregation changes duringthe standing time, and that the viscosity increases. With a standingtime of more than about 120 min, no significant further change in theviscosity was to be observed.

The pharmaceutical administration forms of the invention can preferablybe administered subcutaneously (s.c.) or intramuscularly (i.m.). In thecase of intramuscular administration, the injection takes place forexample into the gluteus maximus muscle, preferably into the upper outerquadrant of the gluteus maximus muscle. In the case of subcutaneousadministration, the injection takes place for example into the subcutisof the abdomen.

The present invention is described in detail in examples 1 to 7 belowwithout restricting the invention thereto.

EXAMPLE 1

200 g of pure D-63153 (calculated as free base) are dissolved in 3386.7g of 30% strength aqueous acetic acid to form a clear solution. 438.4 gof mannitol is added and dissolved by stirring. The solution is made upto a total amount of 20 320 g with water for injections.

After the solution has been sterilized by filtration it is dispensed in10 ml portions into vials for lyophilization.

After the method, each vial contains 100 mg of D-63153 (free base) and109.6 mg of mannitol.

The lyophilizate is reconstituted by adding 4 ml of 0.1% strength sodiumchloride solution and carefully shaking (avoid foaming) in order toobtain a suspension of 25 mg/ml.

EXAMPLE 2

Lyophilizates which contain 75 mg of D-63153 were produced andreconstituted with 3 ml of solvent (25 mg of D-63153/ml). Thereconstitution took place with sterile water for injections (non-depotadministration form; see table 1) or with 0.1% NaCl (depotadministration form; see table 2). A single dose of 1.68 mg/kg wasinjected subcutaneously into beagle dogs. The D-63153 plasma levels weremeasured at various times after administration.

It was possible through the use of the depot administration form toreduce the maximum plasma levels (Cmax), while the area under the curveremained substantially stably maintained, which results in a depoteffect. The absolute bioavailability remained substantially unchangedand was calculated to be 62% for the non-depot administration form, and64.3% for the depot form [Schwahn and Romeis, 1999].

EXAMPLE 3

In order to subrime the D-63153 depot for its testosterone-suppressingpotential, it was injected in 5 different doses (5-25 mg/kg)intramuscularly (i.m.) into male rats. The depot administration form wasgenerated by resuspending D-63153 lyophilizate in 0.1% strength sterileNaCl. The testosterone level was measured before administering themedicament and in each case 4 hours, 8 hours and 24 hours thereafter. Inaddition, the testosterone level was determined once a day in the firstweek after injection and subsequently on every 2nd day, in each caseuntil the testosterone level was again in the normal range. The controlgroup was treated only with a vehicle solution (see FIG. 1). Adose-dependent suppression of the testosterone levels was detectable inall groups. The suppression lasted for from 17 days (5 mg/kg) to 43 days(20 mg/kg) . The testosterone levels were subsequently again within thenormal range within a few days.

EXAMPLE 4

10 mg lyophilizates of D-63153 were reconstituted in 4 ml of sterilewater for injections (non-depot administration form, 2.5 mg/ml D-63153,clinical phase 1a) and 100 mg lyophilizates of D-63153 were dissolved in4 ml of 0.1% NaCl (depot administration form, 25 mg/ml D-63153, clinicalphase 1b). Volunteer male test subjects received intramuscularinjections of 10 mg per person. The D-63153 plasma levels were measuredat various times after administration (see table 3).

The results show that the depot effect can be confirmed both throughlower C_(max) and AUCO₀₋₂₄ plasma levels and through a prolongation oft_(max), t_(1/2) and in particular an increase in the MRT (meanresidence time). The depot administration form has almost the sameAUC_(0-tlast) as the non-depot administration form (887.44 ng*h/mlcompared with 1165.93 ng*h/ml), thus showing that the two compositionshave similar bioavailabilities. Release is slower from the depotadministration form, indicated by a lower c_(max) level and a value forMRT which is more than twice as high.

EXAMPLE 5

Lyophilizates containing 65 mg and 100 mg of D-63153 were produced andreconstituted with solvent to result in a solution which has aconcentration of 25 mg of D-63153/ml. The solvents used were water forinjections, 0.1% NaCl solution and 0.2% NaCl solution. The extent of thechanges in the colloidal properties of the solutions was investigated bymeans of the viscosities thereof. The results are summarized in FIG. 2.

EXAMPLE 6

Lyophilizates containing 100 mg of D-63153 were produced andreconstituted with solvent to result in a solution which has aconcentration of 25 mg/ml. To describe the change in the colloidalsystem that arises after reconstitution, FIG. 3 depicts the viscosity asa function of the standing time or storage time after reconstitution.

EXAMPLE 7

Lyophilizates containing 65 mg of D-63153 were produced andreconstituted with 2.6 ml of a 0.1% strength NaCl solution, and theresulting solution was in one instance administered s.c. to dogsimmediately (standing time: 0 minutes) (see FIG. 4) and in anotherinstance administered s.c. (see FIG. 5) to dogs after one hour afterreconstitution (standing time: 60 min). The D-63153 plasma levels weremeasured over a time of 72 hours.

The colloidal system obtained by aggregation changes during the standingtime in that its viscosity increases. This is associated with a slightchange in the plasma level plots, with the result that the maximumplasma concentration is reduced and the reproducibility of the plasmalevel plots is improved. TABLE 1 (cf. example 2): Pharmacokineticparameters of D-63153 non-depot administration form in beagle dogs, 1.68mg/kg s.c. Pharmacokinetic parameters of D-63153 D = 1.68 mg D-63153 in5.2% aqueous mannitol peptide base/kg C_(max) t_(max) AUC_(norm) n = 4[ng/ml] [h] [ng · h/ml] Mean 216.55 5.0 19434.3 Min 139.16 2.0 15458.0Max 251.90 6.0 22103.8

TABLE 2 (cf. example 2): Pharmacokinetic parameters of D-63153 depotadministration form in beagle dogs, 1.68 mg/kg s.c. Pharmacokineticparameters of D-63153 D-63153 in 5.2% aqueous mannitol/ D = 1.68 mg 0.1%NaCl peptide base/kg C_(max) t_(max) AUC_(norm) n = 4 [ng/ml] [h] [ng ·h/ml] Mean 97.44 7.0 17688.2 Min 64.75 2.0 14445.6 Max 199.62 8.019676.9

TABLE 3 (cf. example 4): Pharmacokinetic parameters of D-63153:comparison between non-depot and depot administration form in volunteermale test subjects, 10 mg/person (0.14-0.17 mg/kg) i.m. c_(max) t_(max)t_(last) AUC_(0-tlast) AUC₀₋₂₄ AUC₀₋₂₄ t_(1/2) MRT Person [ng/ml] [h][h] [ng*h/ml] [ng*h/ml] [%] [h] [h] n 6 6 6 6 6 6 6 6 Non-depot 99.900.50 300.00 1165.93 495.41 42.40 27.60 52.24 Depot 11.02 2.50 360.00887.44 151.05 16.7 50.05 129.36

1. A pharmaceutical gel preparation comprising at least onepharmaceutically active ionic peptide compound mixed in a predeterminedamount of the value X_(optimum) in mg of peptide per ml of thepreparation with an aqueous solution of an inorganic or acetic acid saltin a predetermined concentration of the value Y_(optimum) in %weight/volume, and after the mixing the administration can take placeimmediately, or a standing time of up to about 120 minutes, preferablybetween about 10 to about 120 minutes, particularly preferably betweenabout 15 to 60 minutes is observed, and it being possible for the valueX_(optimum) to be selected by a test method A including the stages ofadministration of various amounts where X_(n) is the number of differentamounts n, where n≧1 in mg of the peptide as a mixture with an isotonicaqueous solution of mannitol onto or to a test system and selection ofthe amount X_(optimum) in mg of peptide per ml of mixture which providedin the experiment the most favorable blood plasma levels of the peptidein the test system in relation to C_(max) the maximum blood plasmaconcentration and t_(max) the time until C_(max) is reached, and theconcentration Y_(optimum) being selected by a test method B includingthe stages of administration of the amount X_(optimum) in mg of peptideper ml of mixture of the peptide as a mixture with aqueous solutionswhich differ in the concentration where Y_(n) is the number of differentconcentrations n, where n≧1 in % weight/volume onto or to a test systemand selection of the concentration Y_(optimum) in % weight/volume wasfixed as the concentration which in the experiment resulted in thehighest value for the plasma concentration C_(active), whereC_(min)<C_(active)>C_(max) where C_(min)=lowest plasma concentration ofthe peptide at which the peptide still has an adequate pharmaceuticaleffect in the experiment while at the same time, it has an influence onthe time t_(active) until the highest concentration in the plasma isreached, where t_(active)>t_(max).
 2. The pharmaceutical preparation asclaimed in claim 1, wherein the pharmaceutically active ionic peptidecompound is cationic.
 3. The pharmaceutical preparation as claimed inclaim 1, wherein the pharmaceutically active ionic peptide compound isanionic.
 4. The pharmaceutical preparation as claimed in claim 1,wherein the pharmaceutically active ionic peptide compound is a mono-,di- or multi-valent cationic or anionic peptide.
 5. The pharmaceuticalpreparation as claimed in claim 1, wherein the pharmaceutically activeionic peptide compound is a mono-, di- or multi-valent ampholyticpeptide.
 6. The pharmaceutical preparation as claimed in claim 1 whereinthe pharmaceutically active ionic peptide compound has a length of from5 to 20 amino acids.
 7. The pharmaceutical preparation as claimed inclaim 1 wherein the pharmaceutically active ionic peptide compound has alength of from 8 to 12 amino acids.
 8. The pharmaceutical preparation asclaimed in claim 1 wherein the pharmaceutically active ionic peptidecompound is a GnRH analog.
 9. The pharmaceutical preparation as claimedin claim 1 wherein the pharmaceutically active ionic peptide compound isa GnRH antagonist.
 10. The pharmaceutical preparation as claimed inclaim 1 wherein the pharmaceutically active ionic peptide compound isselected from the group consisting of cetrorelix, teverelix, abarelix,ganirelix, azaline B, antide, detirelix, ramorelix, degarelix, D-63153or their pharmaceutically active salt of and mixtures thereof.
 11. Thepharmaceutical preparation as claimed in claim 1 wherein thepharmaceutically active ionic peptide compound is the GnRH antagonistD-63153.
 12. The pharmaceutical preparation as claimed in claim 1wherein the inorganic salt or the acetic acid salt is a physiologicallytolerated salt.
 13. The pharmaceutical preparation as claimed in claim 1wherein the aqueous inorganic salt or acetic acid salt is selected fromthe group consisting of sodium chloride, calcium chloride, magnesiumchloride, sodium acetate, calcium acetate, magnesium acetate andmixtures thereof.
 14. The pharmaceutical preparation as claimed in claim1 wherein the mixture of the pharmaceutically active ionic peptidecompound and of the aqueous solution of the inorganic salt or of theacetic acid salt is a liquid suspension or a semisolid dispersion. 15.The pharmaceutical preparation as claimed in claim 1 wherein the amountX of the pharmaceutically active ionic peptide compound is in the rangefrom about 5 to about 50 mg per ml of the total amount of thepharmaceutical preparation.
 16. The pharmaceutical preparation asclaimed in claim 1 wherein the amount X of the pharmaceutically activeionic peptide compound is in the range from about 10 to about 50 mg perml of the total amount of the pharmaceutical preparation.
 17. Thepharmaceutical preparation as claimed in claim 1 wherein the amount X ofthe pharmaceutically active ionic peptide compound is in the range fromabout 20 to about 30 mg per ml of the total amount of the pharmaceuticalpreparation.
 18. The pharmaceutical preparation as claimed in claim 1wherein the amount X of the pharmaceutically active ionic peptidecompound is in the region of about 25 mg per ml of the total amount ofthe pharmaceutical preparation.
 19. The pharmaceutical preparation asclaimed in claim 1 wherein D-63153 is the pharmaceutically active ionicpeptide compound, and the amount X is in the range from about 5 to about50 mg per ml of the total amount of the pharmaceutical preparation. 20.The pharmaceutical preparation as claimed in claim 19 wherein D-63153 isthe pharmaceutically active ionic peptide compound, and the amount X isin the range from about 10 to about 50 mg per ml of the total amount ofthe pharmaceutical preparation.
 21. The pharmaceutical preparation asclaimed in claim 19 wherein D-63153 is the pharmaceutically active ionicpeptide compound, and the amount X is in the range from about 20 toabout 30 mg per ml of the total amount of the pharmaceuticalpreparation.
 22. The pharmaceutical preparation as claimed in claim 19wherein D-63153 is the pharmaceutically active ionic peptide compound,and the amount X is in the region of about 25 mg per ml of the totalamount of the pharmaceutical preparation.
 23. The pharmaceuticalpreparation as claimed in claim 1 wherein the concentration Y of theaqueous inorganic or acetic acid salt solution is equal to or less than0.90 (weight/volume).
 24. The pharmaceutical preparation as claimed inclaim 1 wherein the concentration Y of the aqueous inorganic or aceticacid salt solution is in the range from about 0.01% to about 0.9%(weight/volume).
 25. The pharmaceutical preparation as claimed in claim1 wherein the concentration Y of the aqueous inorganic or acetic acidsalt solution is in the range from about 0.05% to about 0.5%(weight/volume).
 26. The pharmaceutical preparation as claimed in claim1 wherein the concentration Y of the aqueous inorganic or acetic acidsalt solution is about 0.1% (weight/volume).
 27. The pharmaceuticalpreparation as claimed in claim 1 wherein the inorganic salt is sodiumchloride, and in that the concentration Y is equal to or less than about0.9% (weight/volume).
 28. The pharmaceutical preparation as claimed inclaim 1 wherein the inorganic salt is sodium chloride, and in that theconcentration Y is in the range from 0.01% to about 0.9%(weight/volume).
 29. The pharmaceutical preparation as claimed in claim1 wherein the inorganic salt is sodium chloride, and in that theconcentration Y is in the range from 0.05% to about 0.5%(weight/volume).
 30. The pharmaceutical preparation as claimed in claim1 wherein the inorganic salt is sodium chloride, and in that theconcentration Y is about 0.1% (weight/volume).
 31. The pharmaceuticalpreparation as claimed in claim 1 wherein at least one of thepharmaceutically active ionic peptide compound is D-63153, and theinorganic salt is sodium chloride.
 32. The pharmaceutical preparation asclaimed in claim 1 wherein at least one of the pharmaceutically activeionic peptide compound is D-63153, and the amount X thereof is about 25ml per ml of the preparation, and in that the inorganic salt is sodiumchloride, and the concentration Y thereof is about 0.1% (weight/volume).33. A method for producing a pharmaceutical preparation comprising thesteps A) bringing together an amount X_(optimum) in mg per ml of thefinished preparation of at least one pharmaceutically active peptidecompound in lyophilized form and an aqueous solution of an inorganic oracetic acid salt in a concentration with the value Y_(optimum) (%weight/volume) and B) mixing the components.
 34. The method forproducing a pharmaceutical preparation as claimed in claim 33, whereinthe pharmaceutically active ionic peptide compound is D-63153, and theinorganic salt is sodium chloride.
 35. The method for producing apharmaceutical preparation as claimed in claim 33, wherein thepharmaceutically active ionic peptide compound is D-63153, and theamount thereof is about 25 mg/ml, and in that the inorganic salt issodium chloride, and the concentration thereof is about 0.1%(weight/volume).
 36. The method for producing a pharmaceuticalpreparation as claimed in claim 33, further comprising the step ofsterilization of the peptide formulation by irradiation with gamma raysor electron beams takes place.
 37. The method for producing apharmaceutical preparation as claimed in claim 33, where the productionof the peptide formulation takes place with use of aseptic procedures.38. A kit for producing a pharmaceutical preparation, comprising apreviously fixed amount X in mg per ml of the finished preparation of apharmaceutically active ionic peptide compound in lyophilized form andof an aqueous solution of an inorganic or acetic acid salt in apreviously fixed concentration Y % (weight/volume).
 39. The kit asclaimed in claim 36, wherein the pharmaceutically active peptidecompound is D-63153 in lyophilized form.
 40. The kit as claimed in claim36, wherein the D-63153 lyophilizate additionally comprises mannitol.41. The kit as claimed in claim 36, wherein the inorganic salt is sodiumchloride.
 42. The kit as claimed in claim 36 wherein the amount X ofD-63153 is about 25 mg per finished preparation and the concentration ofthe aqueous sodium chloride solution is about 0.1% weight/volume.
 43. Amethod for treating a patient with a pharmaceutically active peptidecompound, wherein a pharmaceutical preparation as claimed in claim 1 isadministered subcutaneously or intramuscularly to the patient by meansof a syringe.
 44. The method as claimed in claim 43 wherein theadministered pharmaceutical preparation displays a sustainedpharmaceutical activity.
 45. The method as claimed in claim 43 whereinthe administered pharmaceutical preparation displays a sustainedpharmaceutical activity for at least 4 weeks.
 46. The method as claimedin claim 43 wherein the administered pharmaceutical preparation displaysa sustained pharmaceutical activity for at least 8 weeks.
 47. The methodas claimed in claim 43 wherein the administered pharmaceuticalpreparation displays a sustained pharmaceutical activity for at least 12weeks.
 48. A method for treating a hormone-dependent disorder in apatient by subcutaneous or intramuscular administration of apharmaceutical preparation as claimed in claim 1 in a patient requiringthis.
 49. A method for treating prostate cancer in a patient bysubcutaneous or intramuscular administration of a pharmaceuticalpreparation as claimed in claim 1 in a patient requiring this.
 50. Amethod for treating breast cancer in a patient by subcutaneous orintramuscular administration of a pharmaceutical preparation as claimedin claim 1 in a patient requiring this.
 51. A method for treatinguterine myomas in a patient by subcutaneous or intramuscularadministration of a pharmaceutical preparation as claimed in claim 1 ina patient requiring this.
 52. A method for treating endometriosis in apatient by subcutaneous or intramuscular administration of apharmaceutical preparation as claimed in claim 1 in a patient requiringthis.
 53. A method for treating precocious puberty in a patient bysubcutaneous or intramuscular administration of a pharmaceuticalpreparation as claimed in claim 1 in a patient requiring this.
 54. Amethod for modifying the reproductive function in a patient bysubcutaneous or intramuscular administration of a pharmaceuticalpreparation as claimed in claim 1 in a patient requiring this.
 55. Thepharmaceutical preparation as claimed in claim 1 wherein the mixture ofthe pharmaceutically active ionic peptide compound and of the aqueoussolution of the inorganic salt or of the acetic acid salt is amolecular-dispersed or colloidal mixture which may be of liquid tosemisolid consistency.
 56. The pharmaceutical preparation as claimed inclaim 1 wherein a colloidal dispersion is formed by reconstitution. 57.The pharmaceutical preparation as claimed in claim 1 wherein a colloidaldispersion is formed by storage or leaving to stand after reconstitutionand changes its viscosity as a function of time and thus improves thereproducibility of the delayed release of active ingredient.
 58. A kitcomprising a lyophilized pharmaceutically active peptide, optionallytogether with one or more pharmaceutically acceptable excipients oradditives, and a low-concentration aqueous solution of an inorganicsalt, preferably sodium chloride.
 59. The kit as claimed in claim 58,wherein the lyophilized pharmaceutically active peptide is D-63153. 60.The kit as claimed in claim 58, wherein the inorganic salt is sodiumchloride.